Incomplete lineage sorting of segmental duplications defines the human chromosome 2 fusion site early during African great ape speciation

Abstract

All great apes differ karyotypically from humans due to the fusion of chromosomes 2a and 2b, resulting in human chromosome 2. Yet, the structure, function, and evolutionary history of the genomic regions associated with this fusion remain poorly understood. Here, we analyze finished telomere-to-telomere chromosomes in great apes and macaques to show that the fusion was associated with multiple pericentric inversions, segmental duplications (SDs), and the rapid turnover of subterminal repetitive DNA. We characterized the fusion site at single-base-pair resolution and identified three distinct SDs that originated more than 5 million years ago. These three distinct SDs were differentially distributed among African great apes as a result of incomplete lineage sorting (ILS) and lineage-specific duplication. Most conspicuously, one of these SDs shares homology to a hypomethylated SD spacer sequence present in hundreds of copies in the subterminal heterochromatin of chimpanzees and bonobos. The fusion in human was accompanied by a systematic degradation of the three divergent -satellite arrays representing the ancestral centromere creating five distinct structural haplotypes in humans. CRISPR/Cas9-mediated depletion of the fusion site in human cell lines significantly alters the expression of 108 genes, indicating a potential regulatory consequence to this human-specific karyotypic change.